N-(3-pyrrolidinyl)-phthalimide derivatives



United States Patent Ofiice 3,316,276 Patented Apr. 25, 1967 3,316,276 N-(3-PYRROLIDINYL)-PHTHALIMIDE DERIVATIVES Grover C. Helsley, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va., a corporation of Virginia No Drawing. Filed Oct. 6, 1965, Ser. No. 494,304 13 Claims. (Cl. 260326) This invention relates to a series of novel N-substituted phthalimide compounds, particularly N-(substituted-3- pyrrolidinyl)-phthalimides, therapeutic compositions containing the same as active ingredients and methods of making and therapeutically administering said compounds and compositions.

The novel compounds described hereinafter have utility as physiologically active agents and particularly as eifective antiarrhythmic agents, therapeutically applicable in the treatment of cardiacarrhythmias.

It is accordingly an object of the present invention to provide novel compounds which have a high degree of antiarrhythmic activity. An additional object is the provision of compounds having antiarrhythmic activity and which produce minimal side effects. Another object is to provide certain novel N (substituted-3-pyrrolidinyl) phthalimides. A further object is to provide a method of using said antiarrhythmic agents in the treatment of living animal and especially mammalian bodies. A still further object is to provide pharmaceutical compositions which embody the said agents. A still further object is to provide a method for preparing said novel N-(substituted-3- pyrrolidinyl)-phthalimides. Additional objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter.

The novel chemical compounds of this invention are represented by the following structure formula:

wherein R is a member of the group consisting of hydrogen, lower alkyl, aryl, aralkyl and alicyclyl; R is a member of the group consisting of hydrogen and lower alkyl; R" is a member of the group consisting of hydrogen, halogen having an atomic weight less than 80, trifluoromethyl, lower alkyl and lower alkoxy; m is -2 and n is 0-4.

The terms lower alkyl and lower alkoxy as used herein include straight and branched chain radicals of from 1 to 4 carbon atoms inclusive.

Examples of lower alkyl radicals are methyl, ethyl, propyl, N-butyl, isopropyl, isobutyl and tertiary butyl. Suitable lower alkoXy radicals are methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Aryl radicals include the unsubstituted phenyl radical and phenyl radicals substituted by any radical or radicals which are not reactive or otherwise interfering under the conditions of the reaction, such as nitro, lower alkyl, trifluoromethyl, halo, and the like. Included in the term .aralkyl are lower-alkyl substituted monocarbocyclic aryl groups such as benzyl, phenethyl, methylbenzyl, phenpropyl, and the like. Alicyclic radicals include such groups as cyclobutyl, cyclohexyl, cyclopentyl, ethylcyclopentyl, and cycloheptyl.

This invention also includes pharmaceutically acceptable acid addition salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or isopropyl ether, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methane-sulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic itaconic, p-aminobe-nzoic, glutamic, stearic and the like. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

In addition this invention includes pharmaceutically acceptable, nontoxic quaternary ammonium salts of the above defined bases. The quaternary ammonium salts are readily formed by treatment of the corresponding free base with the appropriate salt-forming substance, including, for example, methyl chloride, methyl bromide, methyl iodide, methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-propyl iodide, isopropyl iodide, n-butyl chloride, n-butyl bromide, isobutyl bromide, sec-butyl bromide, n-amyl chloride, isoamyl chloride, n-amyl bromide, isoarnyl bromide, n-arnyl iodide, isoamyl iodide, n-hexyl chloride, isoheXyl chlo ride, n-hexyl bromide, isoheXyl bromide, n-hexyl iodide, isohexyl iodide, or similar quaternary salt-forming substances, according to general procedures which are Well known in the art.

It will be readily apparent to one skilled in the art that certain compounds of this invention may be present as optical isomers. The connotation of the general formulas presented herein is to include all isomers, the separated d orl isomers as well as the dl mixtures of these isomers.

In general, the novel compounds of this invention are prepared by reacting a selected 3-halopyrrolidine substituted at one or more positions with a lower alkyl radical or a selected 3-pyrrolidinyl tosylate substituted at one or more positions on the pyrrolidine nucleus with a lower alkyl radical with an appropriately substituted phthalimide compound in the form of its alkali metal salt in accordance with the following graphic equation:

\N Um'nuw a N it n can be prepared in accordance with the methods deibed in Synthesis and Anticholinergic Activity of ter Derivatives of Substituted 3-Pyrrolidinols by Ryan :1 Ainsworth, J. Org. Chem., 27, 2901 (1962), 4-(5- bstituted Ethyl)-3,3-Diphenyl-2-Pyrrolidinones. A new ties of CNS Stimulants by Lunsford et al., J. Med. tern. 7, 302 (1964) and in US. patent application 422,570, filed Dec. 31, 1964, by Carl D. Lunsford d Albert D. Cale, Jr. entitled, Heterocyclic Organic mpounds, Intermediates Therefore and Products and re Thereof, all of which publications are hereby inrporated by reference as if fully set out herein.

The compounds of the present invention are prepared dissolving the substituted 3-halopyrrolidine or the subtuted 3-pyrrolidinyl arylsulfonate in and suspending the etalated substituted phthalimide in a suitable solvent ch as dimethyl sulfoxide, methanol, ethanol, benzene, luene, and the like, which will not enter into the reacn, but which will provide a reaction medium. The nount of solvent used will depend to a certain extent )on the equipment used. Generally speaking, however, out 5 parts of solvent per part of the phthalimide and out 1 to 2 parts of solvent per part of the pyrrolidine mpound are used.

The reactants, dissolved and suspended as described move, are then admixed by treating dropwise over a :riod of about minutes the stirred metalated phthallide suspension at 65115 C. with the desired pyrroline compound. In an alternative method the reactants 1d solvent are mixed together at room temperature.

The resulting reaction mixture is stirred for a period ftime necessary to effect the formation of the N-substi- .ted phthalimide, usually about 16 hours. There is no 'iticality about the temperature of the reaction mixture 1t 110115 C. is the preferred reaction temperature.

Isolation and purification of the compounds of the resent invention is best achieved by stripping the reacon mixture of solvent and distilling the residual oily marial or precipitating the crude product by diluting the )oled reaction mixture with a large excess of water and urifying the compounds from a suitable solvent. Prod- :t work-up by other procedures is also feasible in ac- )rdance with presently available information and such ther methods are equally within the purview of this lvention insofar as they embody the novel methods here- 1 disclosed.

The activity of the pharmacologically active agents of re present invention, as evidenced by tests in mammals indicative of their usefulness for veterinary purposes, nd of similar utility in human beings as well. It will e, however, clearly understood that the distribution and iarketing of any compound or composition falling with- 1 the scope of the present invention for use in human eings will, of course, be subject to prior approval by 1e US. Food and Drug Administration.

The invention is illustrated by the following examples lhlCh, it is to be understood, are merely illustrative and hould not be taken in a limiting sense.

EXAMPLE 1 N-(I-cyclohexyl-3-pyrrolidinyl)-phthalimide To a rapidly stirred suspension of 185 g. (1.0 mole) rf potassium phthalimide in 1000 ml. of dimethyl sulfoxde at 90 C. was added slowly 188 g. (1.0 mole) of 3- :hloro-l-cyclohexyl pyrrolidine. The mixture was heated vith stirring for 16 hrs. at 112-115 C. and then filtered vhile hot to remove the inorganic salt. The crystalline )roduct which separated from the cooled filtrate was colected and dried under vacuum. After crystallization from an iso-octane-benzene mixture the dried product veighed 151 g. (51% yield) and melted at 112.5-114 3. The analytical sample melted at 113-1 14 C. after it Was recrystallized from the same solvent system.

Analysis.-Calculated for C H N O C, 72.45; H, 7.43; N, 9.39. Found: C, 72.53; H, 7.33; N, 9.44.

N-(1-cyclohexyl-3-pyrrolidinyl) phthalimide ethiodide was prepared in 59% yield and melted at 186187.5 C. after several recrystallizations from isopropanol-isopropyl ether.

Analysis.Calculated for CzoHgqINgOgI C, 48.01; H, 5.29; N, 7.00. Found: C, 47.75; H, 5.57; N, 7.22.

The maleate salt was prepared using isopropanol as a solvent and melted at 167168.5 C.

The hydrochloride salt was prepared using isopropanolisopropyl ether as solvents and melted at 191-194" C.

PHARMACOLOGY A male mongrel dog (wt. 9.4 kg.) was anesthetized with intravenous phenobarbital sodium, the thorax was opened between the third and fourth ribs on the right side and the animal artificially respired with a Palmer pump. The Grass polygraph and accessory equipment were used for recording carotid arterial blood pressure, jugular venous blood pressure, the electrocardiogram, respiration, intestinal motility, activity of the urinary bladder and urinary flow. The pericardium was opened and arranged to form a cradle in which the heart rested. Aconitine (0.25 mg.) was injected into the wall of the right atrium. After an arrythmia (usually a 2:1 rhythm with a ventricular rate of at least 200 beats/minute) had been established and persisted for 20 minutes, an aqueous solution of N-( 1- cyclohexyl-3-pyrrolidinyl)phthalimide (cone. 9.4 mg./ ml.) containing 1 equivalent of hydrochloric acid was given by infusion through the femoral vein at a constant rate of 1 mL/Inin. Normal sinus rhythm was restored after a dose of 2 mg./ kg. (18.8 mg.) had been given. In the same dog .a dose of 20 mg./kg. (198 mg.) of the known antiarrhythmic agent Pronestyl failed to cause reversion of aconitine-induced arrthythmia to a normal sinus rhythm.

In a general pharmacodynarnic study the most pronounced effect of N-(1-cyclohexyl-3-pyrrolidinyl)-phthalimide was a relatively transient lowering of the blood pressure.

EXAMPLE 2 N-(1ethyl-3-pyrr0lidinyl)-phthalimide 3-chloro-l-ethylpyrrolidine (264 g.; 2.0 moles) in 250 ml. of dimethyl sulfoxide was added slowly to a rapidly stirred suspension of 370 g. (2.0 moles) of potassium phthalimide in 1500 ml. of dimethyl sulfoxide at C. The reaction mixture was stirred for 16 hours at 110 115 C. and then the solvent was distilled out of the reaction mixture at reduced pressure. The residue was distilled in vacuo and the fraction distilling at 143-145 C./ 0.02 mm. was collected separately. The distillate which crystallized on standing weighed 284 g. (58% yield) and melted at -109 C. Several recrystallizations from isooctane raised the melting point to -112" C.

Analysis-Calculated for C H N O C, 68.83; H, 6.60; N, 11.47. Found: C, 69.11; H, 6.56; N, 11.30.

PHARMACOLOGY A male mongrel dog (10.1 kg.) was anesthetized with intravenous phenobarbital sodium, the thorax was opened between the third and fourth ribs on the right side and the animal artificially respired with a Palmer pump. The necessary equipment as described in Example 1 to obtain a complete pharmacodynamic profile was used. The pericardium was opened and arranged to form a cradle in which the heart rested. Injection of 0.25 mg. of aconitine into the wall of the right atrium produced an arrhythmia (a 2:1 rhythm with ventricular rate of 200 beats/ minute). After the arrhythmia had been established for 20 minutes an aqueous solution of N-(1-ethyl-3-pyrrolidinyl)-phthalimide (cone. 10.1 mg./ ml.) containing 1 equivalent of hydrochloric acid was administered by infusion through the femoral vein at a constant rate of 1 ml./ min. Three aconitine induced arrhythmias were restored to normal sinus rhythm after doses of 2.3 mg./kg. (23.23 mg), 1.3 mg./kg. (13.13 mg.) and 1.5 rug/kg. (15.15 mg.) respec- EXAMPLE 3 N- (1 -methyl-3-pyrr0lidinyl) -phthalimide To a rapidly stirred suspension of 139 g. (0.075 mole) of potassium phthalimide in 400 ml. of dimethyl sulfoxide at 90 C. was added dropwise 90 g. (0.075 mole) of 3- chloro-l-methylpyrrolidine. The mixture was heated with stirring for 16 hours, cooled, and filtered to remove the inorganic salt. The solvent was evaporated and 18 g. of the residual oil (133 g.) was distilled at reduced pressure. The fraction boiling at 116118 C./0.02 mm. was collected. The product which crystallized on standing was recrystallized several times from isooctane. The white compound melted at 9295 C. and weighed 7.0 g. (29% yield). The analytically pure sample melted at 94.5-- 955 C. after crystallization from isopropyl ether.

AnalysiS.-Calculated for C13H14N202: C, H, 6.13; N, 12.17. Found: C, 67.54; H, 6.06; N, 12.19.

EXAMPLE 4 N-(1-is0propyl-3-pyrr0lidinyl)phthalimide A rapidly stirred mixture of 118 g. (0.80 mole) of 3- chloro-l-isopropylpyrrolidine, 148 g. (0.80 mole) of potassium phthalimide and 700 ml. of dimethyl sulfoxide was heated at 110-113 C. for 16 hours and filtered while hot to remove the inorganic salt. The crystalline product which formed when the dark red solution was cooled and treated with ca. 100 ml. of water was collected and washed with cold water. The elf-white crystalline product weighed 105 g. (51% yield) and melted at 130-134 C. Several recrystallizations form isooctane-benzene gave colorless material melting at 134135.5 C.

Analysis.Calculated for C H N O C, 69.74; H, 7.02; N, 10.85. Found: C, 69.59; H, 7.07; N, 10.74.

EXAMPLE 5 N-(] -phenyl-3-pyrr0lidinyl)phthalimide A stirred mixture of 190 g. (0.60 mole) of 1-phenyl-3- pyrrolidinyl tosylate and 111 g. (0.60 mole) of potassium phthalimide in 1000 ml. of dimethyl sulfoxide was heated at 65 C. for 7 hours. The material which separated from the cooled reaction mixture was collected, washed with 50% dimethyl sulfoxide-water and then with Water. A second crop was obtained on further dilution of the filtrate with water and was purified by recrystallization from benzene-petroleum ether (30-60 C.). The pure material melted at 151-153 C.; total yield, 97.7 g. (55%).

Analysis.-Calculated for C H N O C, 73.95; H, 5.52; N, 9.58. Found: C, 73.91; H, 5.45; N, 9.66.

EXAMPLE 6 N-(I-benzyl-3-pyrrolidinyl)-phthalimide To a rapidly stirred suspension of 288 g. (1.23 moles) of potassium phthalimide in 800 ml. of dimethyl sulfoxide at 90 C. was added slowly 240 g. (1.23 moles) of 1-benzyl-3-chloropyrro1idine. The mixture was heated with stirring for 16 hours and then filtered hot to remove the inorganic salt. The crystalline product which separated from the cooled filtrate was collected and dried. The white compound weighed 182 g. (48% yield) and melted at 130132 C. Recrystallization from benzeneisooctane raised the melting point to 131-132" C.

Analysis.Calculated for C H N O C, 74.49; H, 5.92; N, 9.15. Found: C, 74.51; H, 6.01; N, 9.08.

6 EXAMPLE 7 N -(1 -phenethyl-3-pyrr0lidinyl)phthalimide 3-chloro-l-phenylethylpyrrolidine (258 g., 1.23 moles) Was added slowly to a rapidly stirred suspension of potassium phthalimide (288 g., 1.23 moles) in dimethyl sulfoxide (800 ml.) while maintaining the temperature at The heated mixture was stirred for 16 hours and then filtered while hot to remove the inorganic salt. The product was isolated and purified in the usual manner.

EXAMPLE 8 4-chl0ro-N- (1 -cyclohexyl-3-pyrr0lidinyl) -phthalimide EXAMPLE 9 N- (1-phenyl-2-melhyl-3-pyrr0lidinyl) phthalimide To a well-stirred suspension of 114 g. (0.665 mole) of potassium phthalimide in 400 ml. of dimethyl sulfoxide was added slowly 97.5 g. (0.665 mole) of l-phenyl-Z- methyl-3-chloropyrrolidine. The mixture was heated with stirring for 15 hours and filtered while hot to remove the inorganic salt. The product was isolated by concentrating the filtrate, cooling and adding water to the point of crystallization. The product was collected and dried.

EXAMPLES 1041 By following the principles of the manipulative procedures described in the preceding examples and using the alkali metal salt of appropriately substituted phthalimides and various substituted 3-chloropyrrolidines or 3-pyrrolidinyl aryl sulfonates, the following compounds are prepared:

4-trifiuoromethyl-N-( 1-phenyl-3 -pyrro'lidi11yl) -p hthalimide 4-trifluoromethyl-N- 1-cycloheXyl-3 -pyrrolidinyl -phthalimide 4,5-dimethoXy-N-( 1-phenyl-3-pyrrolidinyl) -phthalimide 4-methoXy-N- 1-cycloheXyl-3-pyrrolidinyl) -phthalimide 4-bromo-N-( 1-ethyl-4-methy1-3-pyrrolidinyl)-pl1thalimide 4-bromo-N- 1-ethyl-3-pyrrolidinyl -phthalimide 4-bromo-N- l-cyclohexyl-B-pyrrolidinyl) -phthalimide 4,5-dimethoxy-N-( 1-cyclohexyl-3 -pyrrolidinyl) -phthalimide 4,5-dimethoxy-N-( 1-cyclohexyl-4-methy1-3-pyrrolidinyl phthalimide 4,5-diethyl-N-( 1-ethyl-3-pyrrolidinyl) -phthalimide 4,5-dimethy1-N-(1-ethyl-3 -pyrrolidinyl -phthalimide 4,5-diethyl-N-( 1-phenyl-3 -pyrrolidinyl -phthalimide 4,5-diethyl-N-(4-methyl-1-phenyl-3-pyrrolidinyl)-phtha1- imide 4,5-diethoxy-N-( 1-phenyl-3-pyrrolidinyl)-phthalimide 4,5-diethoxy-N-(4-methyl-1-phenyl-3-pyrrolidinyl) phthalimide 4,5-diethoxy-N-(1-cyclohexyl-3 -pyrrolidinyl) -phthalimide 4,5 -diethoxy-N-( 1-phenethyl-3 -pyrrolid.inyl -phthalimide 4,5-diethoxy-N-( 1-benzyl-3-pyrrolidiny1) phthalimide 4,5 -diethoxy-N- 5 -methyl- 1-pheny1-3 -pyrrolidinyl) phthalimide 4,5-diethoXy-N-( 1-isopropyl-3 -pyrr0lidinyl) -phthalimide 4-methyl-N-( 1,2,2-trimethyl-3-pyrrolidinyl -phthalimide 3-methyl-N- 5 -rnethyl- 1 -pheny1-3 -pyrrolidinyl) -phthalimide 3,5 -dichloro-N-( 1-benzyl-3-pyrrolidinyl -phthalirnide 3 ,4-dibromo-N-(1-benzyl-3-pyrrolidinyl)-phtha1imide 3,4,5,6-tetrachloro-N- 1 -methyl-3 -pyrrolidinyl -phth alimide 7 4,5-trichloro-N- 1-ethyl-3-pyrrolidinyl -phthalimide 4,5 -trichloro-N-( 1,2,2-trimethyl-3 -pyrrolidinyl -phthalimide 5 -dichloro-N-( 1-benzyl-2,2-dimethyl-3 -pyrrolidinyl phthalimide 4,5 -trimethyl-N-( l-ethyl-3 -pyrrolidinyl) -phthalimide ethoxy-N-( 1-phenethyl-4-methyl-3 -pyrrolidinyl) -phthalimide 5-dibromo-N-( 1-phenethyl-4,5-dimethyl-3-pyrrolidinyl) -phthalimide trifiuoromethyl-N-( 1-cyclohexyl-2-methyl-3-pyrrolidinyl -phthalimide.

The invention further provides pharmaceutical comositions comprising, as active ingredients, at least one of 1c compounds according to the invention in association 'ith a pharmaceutical carrier or excipient. The com- Junds are thus presented in a form suitable for oral, :ctal, parenteral or intracardial administration, or in :1 arm suitable for inhalation. Thus, for example, comositions for oral administration are solid or liquid and an take the form of capsules, tablets, coated tablets, JSPCIlSlOIlS, etc., such carriers or excipients conveniently sed in the pharmaceutical art. Suitable tableting excipints include lactose, potato and maize starches, talc, elatin and stearic and silicic acids, magnesium stearate nd polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient an be a sterile, parenterally acceptable liquid, e.g. water, r a parenterally acceptable oil, e.g. arachis oil, contained n ampoules.

In compositions for rectal administration, the carrier an comprise a suppository base, e.g. cocoa butter, or a ;lyceride.

Advantageously, the compositions are formulated as losage units, each unit being adapted to supply a fixed lose of active ingredient. Tablets, coated tablets, capules, ampoules and suppositories are examples of pre- 'erred dosage unit forms according to the invention. Each dosage unit adapted for oral administration may :onveniently contain 25 to 900 mg., and preferably 100 o 500 mg, of the active ingredient; each dosage unit tdapted for intracardial, intravenous, or inhalation adninistration may conveniently contain to 280 mg., and )referably 50 to 200 mg. of the active ingredient; whereas :ach dosage unit adapted for intramuscular administraion may conveniently contain to 400 mg. and pref- :rably 100 to 300 mg. of the active ingredient.

Examples of compositions within the preferred ranges given are as follows:

(1) Dissolve 6 and 7 in hot water.

(2) This solution, when cool, is mixed with #3 and the mixture is stirred until uniform.

(3) Dissolve 1, 2, 4, 5 and 8 in this solution and stir until uniform.

CAPSULES Ingredients: Per cap., mg. (1) Active ingredient 250.000 (2) Lactose 146.000

(3) Magnesium stearate .000

Procedure:

(1) Blend 1, 2 and 3. (2) Mill this blend and blend again. (3) This milled blend is then filled into #1 hard gelatin capsules.

TABLETS Ingredients: Mg. tab., mg.

(1) Active ingredient 200.0

(2) Corn starch 20.0

(3) Kelacid 20.0

(4) Keltose 20.0

(5) Magnesium stearate 1.3

Procedure:

(1) Blend 1, 2, 3 and 4.

(2) Add sufilcient water portionwise to the blend from step #1 with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet granules.

(3) The wet mass is converted to granules by passing it through the oscillating granulator, using 8-mesh screen.

(4) The wet granules are then dried in an oven at (5) The dried granules are then passed through an oscillating granulator, using a 10-mesh screen.

(6) Lubricate the dry granules with 0.5% magnesium stearate.

(7) The lubricated granules are compressed on a suitable tablet press.

INTRAVENOUS INJECTION Ingredients: Per ml. (1) Active ingredient 50.0 mg. (2) pH 4.0 buffer solution q.s. to 1.0 ml.

Procedure:

(1) Dissolve the active ingredient in the buffer solution.

(2) Aseptically filter the solution from step #1.

(3) The sterile solution is now aseptically filled into sterile ampuls.

( 4) The ampuls are sealed under aseptic conditions.

INTRAMUSCULAR INJECTION Ingredients: Per ml. 1) Active ingredient 50.0 mg. (2) Isotonic buffer solution 4.0 q.s. to 2.0 ml. Procedure:

(1) Dissolve the active ingredient in the buffer solution.

(2) Aseptically filter the solution from step #1.

(3) The sterile solution is now aseptically filled into sterile ampuls.

(4) The ampuls are sealed under aseptic conditions.

SUPPOSITORIES Ingredients: Per supp., mg.

(1) Active ingredient 200.0

(2) Polyethylene glycol 1000 1350.0

(3) Polyethylene glycol 400 450.0

Procedure:

( 1) Melt 2 and 3 together and stir until uniform.

(2) Dissolve #1 in the molten mass from step 1 and stir until uniform.

(3) Pour the molten mass from step 2 into suppository molds and chill.

(4) Remove the suppositories from molds and wrap.

INHALATION Ingredients: Amt. cc. (1) Active ingredient mg 100 (2) Alcohol q.s cc 1.0

Procedure:

(1) Dissolve #1 and #2. (2) This solution is properly packaged in an aerosol dispenser containing a metered valve and a suitable propellant.

wherein R is a member selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl and alicyclyl, wherein R is lower alkyl;

wherein R" is a member selected from the group consisting of halogen having an atomic weight less than 80, trifluoromethyl, lower alkyl and lower alkoxyl; wherein m is 0-2 and n is 04, wherein aryl has a maximum of 12 carbon atoms and a phenyl ring with substituents selected from the group consisting of hydrogen, trifluoromethyl, halogen having an atomic weight less than 80, wherein aralkyl has a phenyl-lower alkyl radical and a maximum of nine carbon atoms, wherein alicyclyl has a saturated ring having from four to seven carbon atoms and a maximum of nine carbon atoms and acid addition and quaternary ammonium salts thereof. 2. A compound of the formula wherein R is lower alkyl.

3. A compound of the formula wherein R is lower alkyl and R is lower alkyl.

4. A compound of the formula II o R wherein R is lower alkyl and R" is halogen.

5. A compound of the formula wherein R is lower alkyl, R is lower alkyl and R" is halogen.

6. N-(l-methyl-3-pyrrolidinyl) phthalimide.

7. N-(1-ethyl-3-pyrrolidinyl) phthalimide.

8. N-(1-isopropyl-3-py-rrolidinyl) phthalimide.

9. N (1 isopropyl-2-methyl-3-pyrrolidinyl) phthalimide.

10. 4 chloro N-( 1-isopropyl-3-pyrrolidinyl) phthalimide.

11. 4-chloro-N-(1 isopropyl-Z-methyl-3-pyrrolidinyl) phthalimide 12. N-(1-benzyl-3-pyrrolidinyl) phthalimide.

13. N-(1-cyclohexyl-3-pyrrolidinyl) phthalimide.

References Cited by the Examiner UNITED STATES PATENTS 3,137,705 6/1964 Prelog et al. 260-326 3,201,472 8/1965 Spivack 260--326 ALEX MAZEL, Primary Examiner. NICHOLAS S. RIZZO, Examiner.

MARY U. OBRIEN, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF N-SUBSTITUTED PHTHALIMIDES HAVING THE STRUCTURAL FORMULA: 